Optimizing the Diagnostic Approach to Cephalosporin Allergy Testing

Обзор

Cephalosporin antibiotics are commonly used but can result in allergic reactions and anaphylaxis. There is no clear diagnostic approach for cephalosporin-allergic patients, and guidance for the use of other antibiotics in allergic patients is based on side chain chemical similarity and limited skin testing evidence. This project includes a clinical trial and mechanistic studies to optimize the approach to cephalosporin allergy and advance future diagnostics.

Подробное описание

Background:

In the United States, beta-lactam antibiotics are the leading cause of allergic reactions. Cephalosporin antibiotics, in particular, are the most common cause of drug-induced anaphylaxis and perioperative allergy. For penicillin allergy, the mechanism of allergy and the antigenic determinants are known; validated penicillin skin testing followed by drug challenge has a 100% negative predictive value to exclude an immunoglobulin (Ig)E-mediated reaction. For cephalosporin allergy, the antigenic determinants and mechanism are not known, and skin testing is not validated. The diagnostic test characteristics of skin testing with native cephalosporins remain unclear with no sensitivity nor specificity reported. Although beta-lactam cross-reactivity has been hypothesized to be from the similarity of the R1 side chains, rather than the beta-lactam ring, cross-reactivity estimates among beta-lactams vary. Furthermore, it is not known whether the variance in cross-reactivity is due to true allergy versus sensitization based on positive skin testing, given that drug challenges were not performed on skin-test-positive patients. While an IgE mechanism is assumed for cephalosporin allergy and supported by skin testing that has been positive, the biology has yet to be characterized, and some cephalosporin anaphylaxis can occur on the first exposure, which is inconsistent with an IgE mechanism. Given the complexity of cephalosporin structures and potential epitopes, there may be several distinct biologic pathways involved in cephalosporin allergy. Future diagnostics in cephalosporin allergy are reliant on determination of these biological pathways and finding key haptens.

Aims:

Current national practice guidelines related to cephalosporin allergy assessment are conditional and based on low-quality evidence. The overall goal is to identify the optimal diagnostic approach to cephalosporin allergy and determine beta-lactam cross-reactivity, while discovering the mechanism and antigenic determinants of cephalosporin allergy to advance future diagnostics. The investigators will do this through a clinical trial that will generate empirical evidence through novel trial procedures, double-blind skin testing, and double-blind placebo-controlled drug challenges. Specific aims are: 1) To determine the optimal approach to cephalosporin allergy evaluation; 2) To assess beta-lactam cross-reactivity in cephalosporin-allergic individuals; and 3) To investigate the antigenic determinants and mechanism of cephalosporin allergy.

Study Overview:

Enrolled and consented subjects will attend Visit 1 for baseline screening, sample collection, double-blind skin testing to a beta-lactam panel, and a double-blind placebo-controlled challenge to their culprit cephalosporin antibiotic. Results of the culprit cephalosporin challenge determine subject's study timeline. Subjects confirmed as non-allergic to their culprit cephalosporin will return for the End-of-Study Visit for venipuncture and blood collection, ending their participation in the study. Subjects who are confirmed as allergic to their culprit at Visit 1 will return for three additional visits; Visits 2 and 3 will include double-blind placebo-controlled challenges to a similar side chain and dissimilar side chain cephalosporin (as compared to the side chain of their culprit) to assess cross-reactivity. The order of these two challenges is randomized between Visit 2 and 3, and the order of whether a similar or dissimilar side chain cephalosporin is challenged first (in Visit 2) differentiates the comparator arms of this study. In Visit 4, subjects from both comparator arms will undergo a double-blind placebo-controlled challenge to a penicillin to assess cross-reactivity between cephalosporins and penicillins. After completion of this penicillin challenge, confirmed-allergic participants will return for an End-of-Study Visit. This visit will mark the end of their participation in the study. Venipuncture and sample collection will occur at each visit.

Вмешательства

• Препарат Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing
  Percutaneous and intradermal skin testing will be performed in all participants. Concentrations for percutaneous testing; cefazolin (330 mg/ml), cefuroxime (90 mg/ml), ceftazidime (100 mg/ml), ceftriaxone (100 mg/ml), cefepime (200 mg/ml), pre-pen (undiluted), penicillin G (10,000 U/ml), ampicillin (20 mg/ml) and histamine (6 mg/ml). Concentrations for the first intradermal testing; cefazolin (3.3mg/ml), cefuroxime (1 mg/ml), ceftazidime (1 mg/ml), ceftriaxone (1 mg/ml), cefepime (2 mg/ml), Pre-
• Препарат Culprit cephalosporin (cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime) double-blind placebo-controlled drug challenge
  After double-blind skin testing, participants will undergo a 3-step double-blind placebo-controlled drug challenge to their culprit cephalosporin (the cephalosporin they are suspected to be allergic to, either cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime). The challenges are 1:1 randomized to the order of active drug versus placebo. In Step 1, participants will receive 1:1000 of a full dose of either the culprit d
• Препарат Similar cephalosporin (cefepime, ceftriaxone, cefaclor, cephalexin, cefixime, or cefdinir) antibiotic double-blind placebo-controlled drug challenge
  Participants will undergo a 3-step double-blind placebo-controlled drug challenge to a cephalosporin antibiotic that shares a similar side chain with their culprit. This will be cefepime for those allergic to ceftriaxone, cefaclor for those allergic to cephalexin, cefixime for those allergic to cefdinir, cefdinir for those allergic to cefixime, cephalexin for those allergic to cefaclor or cephadroxil, and ceftriaxone for those allergic to cefepime, cefuroxime, or cefpodoxime. The challenges are
• Препарат Dissimilar cephalosporin (ceftriaxone or cefazolin) antibiotic double-blind placebo-controlled drug challenge
  Participants will undergo a 3-step double-blind placebo-controlled drug challenge to a cephalosporin antibiotic that has a dissimilar side chain to their culprit. This will be ceftriaxone for those allergic to cefazolin, and cefazolin for those allergic to any other cephalosporin. The challenges are 1:1 randomized to the order of active drug versus placebo. In Step 1, participants will receive 1:1000 of a full dose of either the culprit drug or placebo, followed by a 30-minute observation period
• Препарат Amoxicillin double-blind placebo-controlled drug challenge
  Participants will optionally undergo a 3-step double-blind placebo-controlled drug challenge to Amoxicillin. The challenges are 1:1 randomized to the order of active drug versus placebo. In Step 1, participants will receive 1:1000 of a full dose of either the culprit drug or placebo, followed by a 30-minute observation period. In Step 2, participants will receive 1:50 of a full dose of either, followed by another 30-minute observation period. In Step 3, participants are administered the full dos

Первичные конечные точки

• Proportion of participants with confirmed culprit cephalosporin allergy [Срок оценки: Up to 7 weeks]
• Cephalosporin skin test sensitivity and specificity [Срок оценки: Up to 7 weeks]
• Proportion of cross-reactivity to other cephalosporins in confirmed-allergic subjects [Срок оценки: Up to 7 weeks]

Вторичные конечные точки (7)

• Culprit cephalosporin skin test diagnostic characteristics [Срок оценки: Up to 7 weeks]
• Cephalosporin skin test diagnostic characteristic performance differences between risk groups [Срок оценки: Up to 7 weeks]
• Association between patient demographics and confirmed cephalosporin allergy [Срок оценки: Up to 7 weeks]
• Association between patient allergy history and confirmed cephalosporin allergy [Срок оценки: Up to 7 weeks]
• Proportion of nocebo responders [Срок оценки: Up to 7 weeks]
• Cephalosporin-specific antibody levels [Срок оценки: Up to 54 months]
• Cephalosporin-specific antibody binding [Срок оценки: Up to 54 months]

Критерии участия

Критерии включения

• Age 18-70 years old.
• Reaction history consistent with a potential immediate hypersensitivity reaction (pruritus, urticaria, erythema, angioedema, bronchospasm, wheezing, shortness of breath, anaphylaxis, or hypotension) to cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime.
• English speaking or non-English speaking with translation services available.

Критерии исключения

• Severe concomitant medical condition (e.g., unstable coronary artery disease, congestive heart failure, severe chronic obstructive pulmonary disease, poorly controlled asthma, chronic renal failure, cirrhosis, or end-stage liver disease.)
• History of Clostridioides difficile infection
• Chronic spontaneous urticaria or systemic mastocytosis
• Incident reaction required cardiopulmonary resuscitation
• Reaction to 2 or more cephalosporin antibiotics
• Active infection or antibiotic treatment within 7 days
• Treatment with systemic antihistamines or corticosteroids within 7 days
• Treatment with omalizumab or dupilumab within 60 days
• Significant immunosuppression
• Treatment with a beta-blocker or ACE inhibitor within 7 days
• Use of investigational drugs within 60 days of participation
• Anaphylaxis in the last 30 days
• Penicillin anaphylaxis within the past year confirmed with positive penicillin skin tests
• Prison or jail inmates, pregnant women, severe cognitive impairment
• Current, diagnosed, mental illness or current, diagnosed, or self-reported drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements
• Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.
• Inability or unwillingness of a participant to give written informed consent or comply with study protocol

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Перекрёстный дизайн

Маскирование

Четверное слепое

Основная цель

Диагностика

Центры проведения

США · 6 центров

• Mayo Clinic Arizona — Scottsdale
• University of California, San Francisco — San Francisco
• Massachusetts General Hospital — Boston
• Rochester General Hospital — Rochester
• Vanderbilt University Medical Center — Nashville
• University of Texas Southwestern Medical Center — Dallas

Идентификаторы

NCT: NCT06406114 · 2024p000928 · U01AI184071

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗